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7/14/2015
MR Guided Focused Ultrasound Treatment of Tumors in Bone and Soft Tissue
Pejman Ghanouni, MD, PhD
Assistant Professor
Department of Radiology
Stanford University School of Medicine
[email protected]
Physics in action
Painting by Giulio Parigi in 1600, via Wikimedia Commons
Focused ultrasound physics
1
7/14/2015
What is focused ultrasound?
• large area ultrasound
transducer array outside
the body
• focused geometrically or
electronically
• amplification
• high intensities deep
within the body, lower
intensities in intervening
tissues
Why now?
Ultrasound was a therapeutic tool
before it became a diagnostic modality
- physical therapy since 1930s
- focused US used clinically since 1950s
- rapid growth in past 10-15 years
William Fry at the University of Illinois, Champaign, circa 1960,
with a 4-beam high-intensity focused ultrasound applicator for neurosurgery.
Advantages of MR guidance
Target
identification
2
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Advantages of MR guidance
Time
Treatment
verification
during the
procedure
Advantages of MR guidance
Post-procedure
target validation
before MRgFUS
after MRgFUS
Pain from bone metastases is often debilitating
 76% of patients with bone metastases report
moderate to severe bone pain at some point
in their disease
Distribution of Skeletal Mets
 Pain from bone metastases often becomes
refractory to systemic therapies
 External beam radiation therapy (EBRT) is
the current standard for refractory bone pain
 Up to 35% of patients do not experience any
pain relief with EBRT and, in those that
respond, pain recurs in up to 27%
 Patients not treated for bone metastases are
at increased risk for skeletal complications
which impact pain and quality of life (QoL)
Sources: Yau et al., 2006; Hartsell et al, 2005.
3
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Bone metastases are common in many cancers
% Patients Developing Bone Mets
100
80
95
73
>50% patients who die
of cancer have bone
mets
68
Systemic
Therapy
Local
Therapy
Analgesics
60
40
Currently Available Palliation for
Bone Metastases
42 40
36 35
Radiotherapy
Bisphosphonates
20
5
0
MRgFUS
Denosumab
Interventional
Chemotherapy
Surgery
Radioisotopes
>80% total metastases to bone
10
Sources: Skeletal Care Academy; Coleman et al., 2006.
Focused ultrasound bone vs soft tissue treatment
Treatment dictated by the properties of the target tissue
Focal Therapy in Soft Tissue
Ablates only at the focal point
Surface Therapy in Bone
Heats larger area of bone cortex
11
Mechanism of MRgFUS bone treatment
Thermal ablation of nerves within bone provides pain palliation
Bone cortex
absorbs
acoustic
energy
more
efficiently
than soft
tissue
Heat absorption by the bone
cortex transfers to the periosteal
nerves ablating them and relieving
pain
12
4
7/14/2015
MR guided focused ultrasound treatment
MR guided FUS
1. Patient Table
• Docks to 1.5T and 3T MR scanners
• Phased array transducer
2. Operator Console
• Controls all treatment
planning and operation
• Sits next to MR in console
room
3. Equipment Cabinet
Patient table: patient cradle
Ultrasound transducer
Motion
system
5
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Conformal focused ultrasound probe
Pre-treatment imaging
Treatment planning
6
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Treatment planning
Treatment planning
Treatment planning
7
7/14/2015
Treatment planning
Treatment planning
Treatment planning
8
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Treatment planning
Treatment planning
Treatment planning
9
7/14/2015
Treatment planning
Treatment planning
Treatment planning
10
7/14/2015
Treatment
Treatment
Treatment
11
7/14/2015
Post-treatment verification
Prospective clinical experience
Author
N
FU (m)
PR
CR
SD
PD
Pain
Sig AEs
Catane1
13
2
NR
NR
NR
NR
65%
0
Gianfelice2
11
3
54
45
0
0
92%
0
Liberman3
31
4
36
36
24
4
69%
0
Napoli4
18
3
3
13
0
2
84%
0
1. Ann Oncol, 2007 2. Radiology, 2008 3. Ann Surg Onc, 2009 4. Invest Radiol, 2013
Pivotal study of MRgFUS for bone metastases
• Primary Efficacy Endpoints
1.At least 50% of patients on treatment arm will achieve at
least 2 point improvement in pain at 3 months without
increase in medication.
2.The response rate in the treated group will be significantly
greater than the response rate in the sham group.
12
7/14/2015
Pivotal study of MRgFUS for bone metastases
• Secondary Efficacy Endpoints
1.Numerical Rating Scale (NRS) score (0 – 10)
2.Medication use quantified by 24 hour morphine equivalents
3.Quality of life (QoL): BPI-QoL
• Safety Endpoints
Adverse Events (AE's) & Serious Adverse Events (SAE’s)
Inclusion and exclusion criteria
• ≥ 18 years of age with life expectancy ≥ 3 months
• Not candidates for RT
• Tumors were visible on MRI and device accessible
• Distinguishable pain at site of targeted tumor
• Tumors were ≥ 1 cm from skin or major nerves
• Low risk of fracture
• Excluded
• significant comorbidities
• if site needed surgical stabilization
Clinical case
• 78 year old male
• Metastatic melanoma
• Painful osteolytic lesion in right
ischium
• Treated with Cyberknife, with
persistent pain
13
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Clinical case
• 78 year old male with painful
metastatic melanoma lesion in
right ischium
• MRgFUS procedure required 19
sonications, up to 1900 J
average pain score
• <60 min sonication time
9
8
7
6
5
4
3
2
1
0
0
1
4
12
weeks after treatment
Clinical case
14
7/14/2015
Responses by study arm
p < 0.001
NRS decrease durable to 3 months
p < 0.001
Opioid use in responders at 3 months
45
Number of patients
40
35
30
25
20
15
10
5
0
Stopped
Decreased
Stable
15
7/14/2015
Reduction in interference of pain with life
p < 0.001
Patient characteristics
Parameter
MRgFUS
Placebo
N=115 (76%)
N=37 (24%)
Primary Cancer Type
Breast
34 (30%)
19 (54%)
[n (%)]
Prostate
15 (13%)
2 (6%)
Kidney
9 (8%)
2 (6%)
Lung
17 (15%)
4 (11%)
8 (23%)
Other
35 (31%)
Target Lesion Type
Osteoblastic
25 (22%)
6 (17%)
[n (%)]
Osteolytic
59 (53%)
21 (60%)
Mixed
27 (24%)
8 (23%)
Patient characteristics
Parameter
Target Lesion Location Pelvis
MRgFUS
Placebo
N=115 (76%)
N=37 (24%)
70 (63%)
19 (54%)
Sacrum/Coccyx
12 (11%)
6 (17%)
Rib/Sternum
16 (14%)
6 (17%)
Extremities
7 (6%)
3 (9%)
Scapula
7 (6%)
1 (3%)
Prior Radiation Therapy Prior RT to lesion*
49 (44%)
9 (26%)
[n (%)]
Prior RT elsewhere
14 (13%)
2 (6%)
No Prior RT
46 (41%)
24 (69%)
3 (3%)
0 (0%)
[n (%)]
Missing
16
7/14/2015
Safety
47 AEs:
4 SAEs:
• 36 (32.1%) sonication
pain
• 9 (8%) positional pain
• 5 patients stopped early
•
•
Gr 3 skin burn
Neuropathy (hip flexor
weakness)
• 2 fractures in osteolytic
bone lesions (1 away from
treated site)
How does this compare to radiation?
Comparison vs. first line treatment with radiation
BM004 Study
RTOG 97-14*
MRgFUS (%)
8Gy x 1 (%)
3 Gy x 10 (%)
Complete
Responders
23
15
18
Partial
Responders
41
50
48
Non-Responders
36
35
34
Hartsell, WF, J Natl Cancer Inst 2005
Key to treatment success
• “Only” 65% had treatment relief
• Hypothesized that some of the
patients that didn't respond in the
treatment group may not have had
a technically successful treatment.
• Reviewed imaging for all the
patients treated in the trial, looking
for any imaging features that
predict pain relief
•
•
•
•
•
Tumor location and size
Intact cortical bone
Lytic or sclerotic tumor
T2WSI
Enhancement
• Subcortical devascularization
• Presence correlates with pain relief
17
7/14/2015
Key to treatment success
• 87 of 104 patients had the black
band (84% technical success)
• 78 of 87 patients with successful
treatment had pain relief (90%)
• 71 had durable relief (82%)
• 12 of 17 patients without
successful treatment had no pain
relief (70%)
• OR of treatment resulting in pain
relief: 7.2
• OR of successful treatment
resulting in pain relief: 14.4
Key to treatment success
• Examined treatment parameters
for correlation with technical
success
•
•
•
•
Number of sonications
Sonication energy
Total energy delivered per treatment
Energy density on bone
• Black band correlates with %ROT
covered during treatment, which
correlates with response
•
•
•
•
•
CR – 93% coverage
PR – 90%
PR, but not durable – 62%
No response – 66%
No black band – 66%
Tumor control – not necessary, but possible
18
7/14/2015
Tumor control
Tumor control
Treatment criteria
•
Tumors must be in the following locations
– pelvis and posterior lower lumbar spine
– ribs and sternum
– shoulders, arms, and legs
•
Tumors must be visible on MRI
•
Tumors must be accessible to the focused
ultrasound beam
– for example, tumors blocked by extensive
scarring or bowel cannot be treated.
•
The targeted bone must be at least 1 cm from
the skin surface.
19
7/14/2015
Contraindications to treatment
Not a good candidate for the treatment if:
•
Cannot safely undergo MR imaging
•
Have a bone that is fragile and may
break or needs surgery to be stabilized,
or has already been stabilized with
surgical implants
•
Have extensive skin scarring in the areas
that would be treated.
Expanding applications
Benign bone tumors - Osteoid osteoma
20
7/14/2015
Risks of treatment
•
Most common risk is pain or discomfort during treatment due to delivery of sonication
energy
– Relieved through anesthesia and intravenous medications
– Dissipates shortly after each sonication ends
•
Positional pain
•
Nausea or vomiting as a side effect of the narcotic medications
•
Blood in urine or urinary tract infection due to urinary catheter
•
Low grade fever for a few days as a reaction to the ablated tissue
•
Low risk of:
– Skin burns, nerve injury, or bone fracture
– Deep venous thrombosis because of the prolonged stationary position in the MR
scanner
Benefits of treatment
• Single outpatient procedure
• Rapid reduction in pain
• Successful in patients that have
not responded to radiation
• Favorable risk profile
Rapid decline in pain score after treatment
average pain score
• Non-invasive
10
9
8
7
6
5
4
3
2
1
0
0
1
4
weeks after treatment
12
Conclusions
• Relief from painful bone metastases is a significant clinical need
• MRgFUS intervention
• Targeted
• Effective
• 80-90% of those with successful treatment had pain relief
• Minimally invasive
• Nontoxic
• MR image guidance and intervention
– MR thermometry provides safety and treatment verification
• Future directions
– Tumor control
21
7/14/2015
Clinical Background for Soft Tissue Tumors of the Extremities
• Heterogeneous group of tumors arising
from connective tissues
• Natural history
• Benign
• Benign, but locally aggressive
• Malignant
Treatment of soft tissue tumors
• Desmoid tumor:
• Observation
• Useful to differentiate aggressive vs slow-growing tumor
• Surgery and/or radiation therapy
• Medical approaches include: anti-estrogens, NSAIDs, chemotherapy,
targeted therapies
• Cryoablation
• Vascular malformation
• Surgical resection
• Image-guided percutaneous sclerotherapy
• Image-guided ablation – radiofrequency, laser or cryoablation
• Soft tissue sarcoma:
• Surgery alone or in combination with radiation or chemotherapy
• Potentially curative
• Significant adverse events and impact on quality of life
Treatment of desmoid tumors
• Surgery
• Infiltrative tumor, so large
resection needed to achieve
negative margins
• Radiation used to:
• Reduce the rate of local
recurrence
• Treat unresectable tumors
• Palliate pain
• Conservative approach now aims
to preserve function
• Recurrence depends not only
on positive margin as well as
behavior of tumor
Tumor
Hamstrin
g
Muscles
Femora
l
Vessels
Sciatic
Nerve
22
7/14/2015
Treatment of desmoid tumors
Treatment of desmoid tumors
Treatment of desmoid tumors
Local recurrence
23
7/14/2015
Treatment of desmoid tumors
• Surgery
• Infiltrative tumor, so large
resection needed to achieve
negative margins
• Radiation used to:
• Reduce the rate of local
recurrence
• Treat unresectable tumors
• Palliate pain
• Conservative approach now aims
to preserve function
• Recurrence depends not only
on positive margin as well as
behavior of tumor
Treatment of desmoid tumors
• Surgery
• Infiltrative tumor, so large
resection needed to achieve
negative margins
• Radiation used to:
• Reduce the rate of local
recurrence
• Treat unresectable tumors
• Palliate pain
• Conservative approach
• Observation
• Recurrence depends not only
on positive margin but also on
behavior of tumor
Clinical background for soft tissue tumors
• Treatment
•
•
•
•
Surgical resection
Radiation therapy
Chemotherapy
Novel systemic treatments (targeted therapies)
• Side effects
• Surgical morbidity
• Radiation burns, secondary malignancy, fibrosis, chronic edema
• Chemotherapy toxicity
• Clinical need
• Decrease morbidity associated with treating soft tissue tumors
• Primary, recurrent, or palliative treatment
24
7/14/2015
Advantages of MR guidance
Targeting
and safety
Advantages of MR guidance
Postprocedure
validation
Example of desmoid tumor treatment
25
7/14/2015
Example of desmoid tumor treatment
A
C
B
D
Example of desmoid tumor treatment
Example of desmoid tumor treatment
26
7/14/2015
Other treatment sites
A
C
Knee and hand
B
D
120
250
300
60
100
200
250
50
200
40
150
30
80
150
60
100
40
20
50
50
0
0
0
Total tumor volume (mL)
-4 -2 0 1 4 5 8 1213161923
-8 -5 0 2 8 12 19 21 27
1200
50
10
1000
40
8
30
6
20
4
800
600
400
10
*
200
250
-8 -4
0
1
3
5
0
1.5
5
8
10
8
150
6
100
4
*
50
2
0
0
-2
0
2
3
7
-12
35
30
25
20
15
10
5
0
-4
0
0
11
38
-3
0
3
9
0
5
23
33
0
2
2.5
11
-29 -16
35
30
25
20
15
10
5
0
*
-8
50
6
9 12 15
36
0
-3
1.5
8
0
4
13
18
8
28
1000
140
120
100
80
60
40
20
0
100
1
-6
4
150
0
4
350
300
250
200
150
100
50
0
350
300
250
200
150
100
50
0
10
200
0
0
0
-3
9 12
10
-20 -11 -8
2
0
0
20
100
800
600
400
200
0
24
0
1
3
6
12
-5
-2
0
1
6
Time relative to first treatment (months)
200
120
100
150
80
60
40
0
Viable tumor volume (mL)
40
-8 -5 0
2
8 12 19 21 27
-20 -11 -8
10
1000
40
8
*
0
-8 -4
0
1
3
5
0
4
0
9 12 15
350
6
200
4
150
10
2
0
0
10
200
8
0
1.5
5
8
10
350
6
200
4
150
50
2
0
3
0
2
3
-4
0
4
-8
120
140
30
100
120
60
15
0
0
0
38
33
10
5
0
36
1000
4
8
8
13
18
28
0
1.5
800
400
20
11
23
600
20
6
5
60
40
5
1
0
80
10
0
0
100
80
20
*
0
-12
35
25
-3
25
20
15
50
0
7
9
35
30
100
-2
-29 -16
0
-3
250
100
0
9 11 14 20
50
-6
300
150
*
3
100
-3
250
1
250
20
9 12
-4 -0.5 0
300
30
600
200
10
0
50
400
20
50
1200
800
30
100
0
-4 -2 0 1 4 5 8 1213161923
50
250
150
50
20
300
200
100
40
0
2
2.5
11
24
200
0
0
1
3
6
12
-5
-2
0
1
6
Time relative to first treatment (months)
27
7/14/2015
Treatment summary
•
Four sites, 15 patients, 26 treatments
•
Average follow-up: 17.5 months (4 – 38 months)
•
Patient age: 28 years (7 – 66 years)
•
Anesthesia: GA, regional, regional + GA, local +
conscious sedation
•
Sonications per treatment: 90 ± 47 (17 – 235)
•
Treatment time: 3.5 hours (0.8 – 8 hours)
•
Spot energies: 1428J (419 – 2867J)
•
Spot temperature: 58 ± 5°C
•
Median total tumor volume: 212 mL (4 – 1010 mL)
•
Average NPVR: 69% (95% CI: 61-77%)
•
Pain relief:
•
•
Max: 7.5 ±1.9  2.7 ± 2.6 (p < 0.0002)
Avg: 6 ± 2.3  1.3 ± 2 (p < 0.003)
Adverse events
• 1st or 2nd degree skin burn
• 8 of 26 treatments
• Non-target ablation
• 3 of 26 treatments
• Nerve injury
• 3 of 26 treatments
Clinical Background for Vascular Malformations
• Heterogeneous group of tumors arising
all over the body
• Most common cause of pediatric
soft tissue tumors
• Vascular malformations are classified
based on flow dynamics
• High flow – AVM or AVF
• Low flow – venous, lymphatic
capillary, or mixed
• Grow proportionally with the patient
• Exacerbated by hormonal changes
during puberty or pregnancy, or by
trauma or infection
28
7/14/2015
Soft Tissue Vascular Malformations
Venous malformations
• Most common vascular malformation
• Location
• Head and neck (40%)
• Trunk (20%)
• Extremities (40%)
• Composition
• Large dysplastic thin walled vascular
channels with sparse smooth muscle and
abnormal stroma, and thrombi and
phleboliths
• Connect with adjacent physiologic veins
• Invade across adjacent tissues
• Presentation
• Congenital, but symptomatic in late childhood
or early adulthood
• Symptoms vary with depth of lesion
• Pain
• Impaired mobility
• Skeletal deformity
Soft Tissue Vascular Malformations
Standard treatment for slow flow lesions
• Surgical resection – 90% success
• Image-guided percutaneous sclerotherapy – 65-90% success
• Image-guided percutaneous radiofrequency, laser or
cryoablation
Treatment summary
Patient age
44 years
Anesthesia
General a/o regional
Follow up
5.5 months
18 – 66 years
3 – 12 months
53
14 – 92
2.5 hours
1 – 4 hours
Sonication energies
1700 J
650 – 2500 J
Power
187 W
97 – 253 W
9.7 s
7.6 – 13.2 s
Sonication number
Treatment time
Sonication duration
Spot temperature
Total tumor volume
Maximal tumor diameter
NPV
NPVR
50°C (avg)
56°C (max)
17.6 mL
0.4 – 61 mL
5 cm
1.4 – 11.4 cm
21.7 mL
6.1
1.05 - 13
29
7/14/2015
Patient #1
7/24/13
12/22/13
Pre-surgery
Pain = 7
Post-surgery
Pain = 8
3/13/14
6/19/14
Post-MRgFUS
Pain = 0
Adverse events
• No skin burn or nerve injury
• Non-target ablation
• Fascia
• Bone
• Fat
Soft tissue sarcoma treatment
30
7/14/2015
Soft tissue sarcoma treatment
Coronal Post-Contrast MRI
Sagittal Post-Contrast
MRI
Pre-MRgHIFU
Post-MRgHIFU
Soft tissue sarcoma treatment
Soft tissue sarcoma treatment
Coronal
Axial
Pre-MRgHIFU
Post-MRgHIFU
31
7/14/2015
Soft tissue sarcoma treatment
Coronal
Axial
Pre-MRgHIFU
Post-MRgHIFU
Soft tissue sarcoma treatment
Coronal
Axial
Pre-MRgHIFU
Post-MRgHIFU
Soft tissue sarcoma treatment
Sagittal
Axial
Pre-MRgHIFU
Post-MRgHIFU
32
7/14/2015
Sarcoma treatment summary
•
5 patients
•
Patient age: 54 years (28– 70 years)
•
Anesthesia: regional
•
Sonications per treatment: 57 (34 – 81)
•
Treatment time: 2 hours (1 – 3 hours)
•
Spot energies: 1506 J (679 – 2985 J)
•
Spot temperature: 56 ± 4°C (avg); 67 ± 10°C
(max)
•
Median total tumor volume: 104 mL (31 – 205 mL)
•
Median NPV: 35 mL (7 – 101 mL)
•
Average NPVR, total volume: 47% (14 – 97%)
•
Average NPVR, planned volume: 818% (0.72 – 36.1)
Challenges
• Positioning
• Coupling to transducer
• Anesthesia
• Higher frequency transducer
• MRI artifacts
• Side effects from far-field
• Cooling mechanism
• More accurate thermometry
• Volumetric, with cumulative dose
• Temperature in fat
• More conformal treatment
planning
Conclusions
• Histologic feedback from sarcoma treatments will improve our
ability to plan treatments, perhaps allowing us to treat recurrences
or to avoid surgery
• Preliminary experience suggests that MRgFUS can be used to
achieve durable local control of desmoid tumors
• Early experience suggests that MRgFUS can be used to achieve
durable local control of small slow-flow vascular malformations
• So far, good safety profile, but need larger number of patients
33
7/14/2015
Conclusions
34